Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

Table 2 In vivo effects of natural terpenoids on development and growth of liver cancer

Terpenoids	Compounds	Effects	Mechanisms	Dose/duration	Route	Ref.
Monoterpenoids	Auraptene	Suppressed DENA-induced TGF-α foci and carcinoma in male F344 rats	↑apoptosis; ↓cell proliferation	100-500 ppm; 7 wk	Diet	Sakata et al[128]
	Geraniol	Decreased GSTp foci and nodules during DENA-initiated and 2-AAF-promoted hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↑apoptosis	25 mg/100 g; 8 wk	po	Ong et al[129]
		Inhibited liver carcinogenesis with decrease in mean number of GSTp foci and nodule induced by DENA and promoted by PB in male Wistar rats	↑apoptosis; ↓RhoA activation	25 mg/100 g; 5 wk	po	Cardozo et al[130]
	d-Limonene	Decreased the number of GSTp foci in DENA-initiated and Glu-P-1-promoted hepatocarcinogenesis in male F344 rats		0.5%; 6 wk	Diet	Hirose et al[131]
		Exhibited chemopreventive effects against DENA/PB hepatocarcinogenesis in male AKR mice	↓c-jun; ↓c-myc	5%; 80 d	Diet	Giri et al[132]; Parija et al[133]
		Reduced the incidence, number and size of GSTp foci and neoplastic nodules induced by NNM in male Sprague-Dawley rats	↑apoptosis; ↓cell proliferation	1%, 2%; 7 wk	Diet	Kaji et al[134]
		Suppressed hepatic preneoplasia and tumor growth induced by DENA in male WR rats	↑GJIC	3 mL/kg per day; 5 times/wk; 5.5 mo	po	Bodake et al[135]
	Perillyl alcohol	Inhibited liver tumor growth induced by DENA in male F344 rats	↑ apoptosis; ↑TGFβ; ↑M6P/IGFII R; ↑TGFβ type I, II, III R	1% w/w for 1 wk and 2% w/w for 18 wk	Diet	Mills et al[136]
Diterpenoids	Andrographolide	Suppressed the formation of BHC- induced nodules in Swiss male albino mice	↑GSH; ↑GR; ↑GPX; ↑SOD; ↑CAT; ↓GGT; ↓GST	5-10 mg/kg per day; 1-8 mo	po	Trivedi et al[137]
		Reversed histomorphological and ultrastructural changes during BHC-induced hepato-carcinogenesis male Swiss mice	↑G-6-Pase; ↑ATPase; ↑SDH; ↓SGPT; ↓SGOT; ↓ALP; ↓OCT; ↓ACP	5,7 and 10 mg/kg; 1-8 mo	Diet	Trivedi et al[138]
	Epoxy clerodane diterpene	Reduced incidence, multiplicity and size of nodules induced by DENA in male Wistar rats	↓SGOT; ↓SGPT; ↓LDH; ↑SOD; ↑CAT; ↓GST; ↓GGT; ↑GSH; ↑GPX	10 mg/kg per day; 8 wk	po	Dhanasekaran et al[139]
	Excisanin A	Suppressed tumor growth in BALB/c nude mice implanted with Hep3B cells	↓apoptosis; ↓pAKT	10-20 mg/kg; 12 d	ip	Deng et al[70]
	Geranylgeraniol	Reduced the incidence, number and size of visible nodules and GSTp foci in DENA/2-AAF hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↓DNA strand break; ↓plasma cholesterol; ↓NF-κB p65	8-16 mg/kg per day; 7 wk	po	de Moura Espíndola et al[140]
Triterpenoids	Bacoside A	Delayed the development and growth of neoplastic nodules induced by DENA in male Wistar albino rats	↓lipid peroxidation; ↑Vit A; ↑Vit E; ↑GSH; ↓ROS; ↓AFP; ↓CEA; ↓5’-nucleotidase; ↓ALT; ↓AST; ↓LDH; ↓ALP; ↓GGT; ↑SOD; ↑CAT; ↑GPX; ↑GR; ↓MMP-2; ↓MMP-9	15 mg/kg; 16 wk	po	Janani et al[141,142]
	Cucurbitacin B	Decreased HepG2 tumor volume and inhibited tumor growth in mice xenograft model		26-110 µg/kg per day; 12 d	po	Zhang et al[83]
		Inhibited tumor growth in BEL-7402 xenografted mice model		0.1-3 mg/kg; twice per day for 26 d	po	Chan et al[84]
	Escin	Demonstrated inhibitory effects on tumor growth in H22 tumor- bearing female Kunming mice		1.4-2.8 mg/kg; 7 d	ip	Zhou et al[88]
	Ginseng extract	Inhibited AFB1-initiated and FB-promoted hepatocarcinogenesis in female SD rats	↓ALT; ↓AST; ↑albumin; ↓TG; ↓cholesterol; ↓LDL; ↑HDL; ↓AFP, ↓CEA, ↓MDA, ↑TAC; ↓fibrosis	150 mg/kg; 1-12 wk	po	Abdel-Wahhab et al[145]
	Glycyrrhizin	Decreased the incidence of nodules and HCC induced by DENA in BALB/c mice	↑albumin; ↑AST	2 mg/animal; 3 d/wk for 12-32 wk	im	Shiota et al[146]
		Reduced the size, volume and number of preneoplastic liver lesions initiated by DENA and promoted with 2-AAF in male SD rats		0.1% 25 mg/kg; 1 wk	po	Wan et al[147]
	EC-2, EC-4	Failed to show modifying effects against DENA-induced hepato-carcinogenesis in male F-344 rats		1 mg/kg; 5 times a week for 2-8 wk	po	Karim et al[148]
	Squalene	Failed to exhibit chemoprevention against DENA-initiated and 2-AAF- promoted hepatocarcinogenesis in male Wistar rats	↑ plasma cholesterol	1-1.5 g/kg; 8 wk	po	Scolastici et al[149]
	Ursolic acid	Inhibited the growth of H22 hepatoma implanted in male CD-1 mice		15-30 mg/kg; 10 d	ip	Tian et al[109]
		Suppressed DENA-initiated and PB- promoted hepatocarcinogenesis in male Wistar rats	↓MDA; ↓PC; ↓membrane damage; ↑Na+K+ ATPase; ↑Mg2+ ATPase; ↑Ca2+ ATPase	20 mg/kg per day; 6 wk	po	Gayathri et al[150]
	Waltonitone	Delayed the growth of tumors in athymic nude BALB/c nu/nu mice implanted with BEL-7402 cells	↑cleaved caspase-3, -9; ↓pro-caspase-9	20-50 mg/kg; Once in 2 d for 15 d	iv	Zhang et al[111]
Tetraterpenoids	α-Carotene	Decreased the number of hepatomas during spontaneous hepatocarcinogenesis in male C3H/He mice		0.005%-0.05%; 40 wk	dw	Murakoshi et al[151]
		Reduced the number of liver tumors in multi-organ carcinogenesis in male and female B6C3F1 mice		0.4 mg/mouse; three times a week for 24 wk	po	Tsuda et al[152]
	β-Carotene	Failed to have an effect on the number and size of preneoplastic liver foci induced by DENA/2-AAF/PB in male Wistar rats		300 mg/kg diet or 10 mg/kg bw (3 times/wk); 3 wk	Diet; ip	Astorg et al[153]
		Failed to exhibit any effect on 2-NP- or DENA-initiated hepato- carcinogenesis in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Astorg et al[154]
		Did not modify DENA-initiated and PCB-promoted hepatocarcinogene-sis in female Sprague-Dawley rats		0.5%; 12 wk	Diet	Tharappel et al[155]
		Inhibited the development of preneoplastic foci and nodules initiated with DENA and promoted by 2-AAF in male Wistar rats		70 mg/kg; alternate d for 2-8 wk	po	Moreno et al[156]
		Reduced the generation of nodules and GGT foci induced by DENA/2-AAF in male Wistar rats		70 mg/kg; 8 wk	po	Moreno et al[157]
		Decreased the incidence and total number of GGT foci and nodules in DENA-initiated and 2-AAF-promoted hepatocarcinogenesis in male Wistar rats	Remodeling of lesions	70 mg/kg; 5 wk	po	Rizzi et al[158]
		Attenuated the development of GSTp foci in the resistant hepatocyte model in male Wistar rats	↓oval cell reaction	70 mg/kg; alternate d for 8 wk	po	Dagli et al[160]
		Suppressed progression of hepatocarcinogenesis induced by DENA in male Wistar rats	↓cell proliferation	70 mg/kg; 8 wk	po	Moreno et al[161]
		Exerted chemoprevention of initiation phage of DENA-induced hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↓DNA damage; remodeling of lesions	70 mg/kg; 8 wk	po	Ambrogi et al[162]
		Conferred a weak chemopreventive effect against DMH-initiated hepatocarcinogenesis in male Wistar rats		70 mg/kg; 9 wk	po	Sampaio et al[163]
		Decreased the incidence, number and size of nodules induced by 2-AAF in male Sprague-Dawley rats	↑cyt. b5; ↑CYP; ↑NADPH cyt. c reductase; ↑AHH; ↓UDPGT; ↓GST	100 mg/kg diet; 4-20 wk	Diet	Sarkar et al[164]
		Suppressed 3’-Met-DAB-induced nodulogenesis in male Sprague-Dawley rats	↓GSH; ↓GGT; ↓GST; ↓GPX; ↓GR; ↑Vit A	120 mg/kg diet; 4-20 wk	Diet	Sarkar et al[165]
		Decreased DENA-initiated and PB-promoted nodule incidence and area in male Sprague-Dawley rats	↓RBC protein damage; ↓lipid peroxidation; ↑G-6-Pase; ↓SOD; ↓CAT	120 mg/kg diet; 4-20 wk	Diet	Sarkar et al[166]
		Suppressed DENA-induced hepatic chromosomal aberrations in male Sprague-Dawley rats	↓frequency of chromosomal aberrations; ↓DNA chain breaks	120 mg/kg per day; 15-45 d	Diet	Sarkar et al[167]
		Reduced the incidence, total number, multiplicity and size of nodules in DENA/PB hepato-carcinogenesis in male Sprague-Dawley rats	↓GSH; ↓GGT; ↓GPX; ↑CYP; ↑GST	500 mg/kg; 4-20 wk	po	Bishayee et al[168]
		Decreased the number and size of GSTp foci in IQ-initiated and PB- promoted hepatocarcinogenesis in male Fischer rats		0.02%; 8 d	Diet	Tsuda et al[169]
		Inhibited the development of GSTp foci and HCC induced by EE in female Wistar rats		250 mg/kg diet; 1-12 mo	Diet	Ogawa et al[170]
		Reduced the development of GSTp foci in Glu-P-1-induced hepato-carcinogenesis in male F344 rats		0.1%; 6 wk	Diet	Hirose et al[131]
		Inhibited carcinogen-DNA adduct formation induced by IQ in male F344 rats	↓CYP1A1; ↓CYP1A2	0.02%; 8 d	Diet	Uehara et al[171]
		Reduced the number of liver tumors in multi-organ carcinogenesis in male B6C3F1 mice		0.4 mg/mouse; three times a week for 24 wk	po	Tsuda et al[152]
		Reduced AFB1-induced hepato-carcinogenesis in male Wistar rats		300 ppm; 3 wk	Diet	Gradelet et al[172]
		Decreased the number and volume of GSTp foci initiated by AFB1 in male Wistar rats		300 mg/kg diet; wk	Diet	Gradelet et al[173]
		Inhibited liver tumor formation induced by DMBA in both male and female toads		0.05 mg/toad; twice a week for 12 wk	sc	Sadek et al[174]
		Suppressed the formation of GSTp foci and nodules initiated with DENA and promoted by PB in male Sprague-Dawley rats	↓GSH; ↓GST; ↑O2 consumption	120 mg/kg; 16 wk	Diet	Chattopadhyay et al[175]
		Reversed histomorphological changes during DENA-induced hepatocarcinogenesis in male Sprague-Dawley rats	↓DNA SSB; ↓K; ↑Ca; ↓Mn; ↓Fe; ↑Cu; ↑Zn; ↓Se	120 mg/kg; 16 wk	Diet	Chattopadhyay et al[176]
	Carotenoids (astaxanthin, β-apo-8’-carotenal, canthaxanthin)	Did not modify DENA/2-AAF/PB hepatocarcinogenesis in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Astorg et al[153]
		Failed to exhibit any effect on 2-NP- or DENA-initiated liver carcinogenesis in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Astorg et al[154]
		Attenuated the number and size of GSTp foci induced by AFB1/2-AAF in male Wistar rats	↓DNA single strand breaks	300 ppm; 3 wk	Diet	Gradelet et al[172]
		Reduced initiation of liver carcinogenesis by AFB1 in male Wistar rats	↓AFB1-DNA binding; ↓DNA single strand breaks; ↑AFB1 metabolism	300 mg/kg diet; 3 wk	Diet	Gradelet et al[173]
	β-Ionone	Reduced the incidence, number and size of GSTp foci and nodules in the initial phase of DENA/2-AAF hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↓plasma cholesterol; ↓DNA damage	80 160 mg/kg; 7 wk	po	de Moura Espíndola et al[140]
		Inhibited GSTp foci and nodules during promotional phase of DENA/2-AAF hepatocarcino-genesis in male Wistar rats	↓cell proliferation; ↓HMGCoA reductase	160 mg/kg; 5 wk	po	Cardozo et al[130]
	Lutein	Reduced the number and size of GSTp foci initiated by DENA and promoted with 2-AAF in male Wistar rats	↓DNA strand breaks	70 mg/kg per day; 8 wk	po	Toledo et al[181]
		Reduced the size of nodules during the promotional phase of DENA/2-AAF hepatocarcinogenesis in male Wistar rats	↓DNA damage	70 mg/kg; 2-6 wk	po	Moreno et al[182]
	Lycopene	Failed to modify AFB1-induced hepatocarcinogenesis in male Wistar rats		300 ppm; 3 wk	Diet	Gradelet et al[172]
		Exhibited no effect on the initiation of hepatocarcinogenesis induced by AFB1 in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Gradelet et al[173]
		Failed to influence the risk of developing spontaneous HCC in male Long-Evans Cinnamon rats		0.005% w/w; 70 wk	Diet	Watanabe et al[183]
		Decreased the volume of GGT and GSTp foci in DENA-initiated and 2-AAF-promoted liver carcinogenesis in male Wistar rats	↓CYP2E1	300 mg/kg diet; 3 wk	Diet	Astorg et al[154]
		Attenuated the number and size of GSTp foci initiated by DENA and promoted with 2-AAF in male Wistar rats	↓DNA strand breaks	70 mg/kg per day; 8 wk	po	Toledo et al[181]
		Decreased the number of GSTp foci in DENA-initiated and PCB-promoted hepatocarcinogenesis in female Sprague-Dawley rats		1%; 12 wk	Diet	Tharappel et al[155]
		Inhibited DENA-initiated and NASH-promoted GSTp foci development in male Sprague-Dawley rats	↓PCNA; ↓cyclinD1; ↓lipid peroxidation; ↑Nrf2; ↑HO-1; ↓pERK; ↓NF-κB p65	15 mg/kg per day; 6 wk	Diet	Wang et al[184]
	Tomato extract	Reduced the number of GSTp foci initiated by DENA and promoted by NASH in male Sprague-Dawley rats	↓PCNA; ↓cyclinD1; ↓TNF-α; ↓IL-1β; ↓IL-12; ↓lipid peroxidation; ↓CYP2E1; ↓pERK; ↓NF-κB	250 mg/kg per day; 6 wk	Diet	Wang et al[184]
Sesquiterpenoids	Dehydrocostus-lactone	Inhibited tumor growth in nude mouse implanted with PLC/PRF/5 cells	↑apoptosis; ↑pPERK; ↑IRE-1	10 mg/kg per day; 45	ip	Hsu et al[124]
	Farnesol	Suppressed the development of GSTp foci and nodules initiated with DENA and promoted by 2-AAF in male Wistar rats	↓cell proliferation; ↓DNA damage; ↓plasma cholesterol; ↓HMG-CoA reductase	250 mg/kg; 8 wk	po	Ong et al[129]
	Zerumbone	Reduced DENA/2-AAF- induced hepatocarcinogenesis in Sprague- Dawley rats	↓ALP; ↓ALT; ↓AST; ↓AFP; ↓lipid peroxidation; ↓GSH; ↓PCNA; ↑Bax; ↓Bcl-2	15, 30 or 60 mg/kg; twice a week for 11 wk	ip	Taha et al[186]

2-AAF: 2-acetylaminofluorene; AFB-1: Aflatoxin B1; AFP: α-fetoprotein; AHH: Aryl hydrocarbon hydroxylase; AHF: Altered hepatic foci; ALA-S: δ-aminolevulinate synthetase; ALP: Alkaline phosphatase; ALT: Alanine transaminase; AST: Aspartate transaminase; BHC: Benzene hexachloride; CA: Chromosomal aberrations; CAT: Catalase; CEA: Carcinoembryonic antigen; CYP: Cytochrome P-450; CYP2E1: Cytochrome P-450 2E1; DAB: 1,4,-dimethylaminoazobenzene; DENA: Diethylnitrosamine; DMH: 1,2-dimethylhydrazine; dw: Drinking water; EAF: Enzyme altered foci; EC-2: 3,4-Seco-8βH-ferna-4-(23),9(11)-dien-3-oic acid; EC-4: 3,4-Seco-oleana-4-(23),18-dien-3-oic acid; EE: Ethynlyestradiol; ERK: Extracellular signal-regulated kinase; FB: Fumonisin; GGT: γ-glutamyl transpeptidase; GJIC: Gap-junctional intercellular communication; Glu-P-1: 2-amino-6-methyldipyrido[1,2-α:3’,2’-d] imidazole; G-6-Pase: Glucose-6-phosphatase; GPX: Glutathione peroxidase; GR: Glutathione reductase; GSTp: Glutathione S-transferase, placental form; GSH: Reduced glutathione; HCC: Hepatocellular carcinoma; HDL: High-density lipoprotein; HO-1: Heme oxygenase-1; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; HTHQ: 1-O-hexyl-2,3,5-trimethylhydroquinone; IL: Interleukin; ip: Intraperitoneal; po: Per os; im: Injectio intramuscularis; sc: Subcutaneous route; IQ: 2-amino-3-methylimidazo[4,5-f]quinoline; JNK: c-Jun N-terminal kinase; LDH: Lactate dehydrogenase; LDL: Low-density lipoprotein; MAPK: Mitogen-activated protein kinase; MDA: Malondialdehyde; M6P/IGFII-R: Mannose 6-phosphate/insulin-like growth factor II receptor; 3’-Met-DAB: 3’-methyl-4-dimethlyaminoazobenzene; MMP: Matrix metalloproteinase; MPE: Mango pulp extract; NASH: Nonalcoholic steatohepatitis; NF-κB: Nuclear factor κB; NMDA: N-nitrosodimethylamine; NNM: Nitrosomorpholine; NMU: N-nitrosomethyl urea; 2-NP: 2-nitropropane; Nrf2: NF-E2-related factor 2; OCT: Ornithine carbamoyltransferase; PB: Phenobarbital; PC: Protein carbonyl; PCB: 3,3′,4,4′-tetrachlorobiphenyl; PCNA: Proliferating cell nuclear antigen; RBC: Red blood cell; ROS: Reactive oxygen species; sc: Subcutaneous; SD: Sprague-Dawley; SDH: Succinate dehydrogenase; SGPT: Serum glutamic pyruvic transaminase; SGOT: Serum glutamyl oxalate transaminase; SOD: Superoxide dismutase; SSB: Single stranded breaks; SULT-1: Sulfotransferase-1; TAC: Total antioxidant capacity; TAT: Tyrosine ketoglutarate; TG: Triglyceride; TGF: Transforming growth factor; TNF: Tumor necrosis factor; Vit: Vitamin; YY1: Ying Yang 1 protein.